DESCRIPTION: The goal of this application is to determine the mechanisms leading to the overexpression of the urokinase receptor (u-PAR) in invasive colon cancer. In Specific Aim 1, the applicant proposes to identify the role of an upstream AP-1 motif in the regulation of u-PAR expression and also identify transcription factors bound by this sequence. Aim 2 will ascertain the role of these promoter regions in regulating u-PAR expression by determining if deletion of either region impairs u-PAR promoter activity, by identifying the nucleotides contacted by nuclear proteins, and by determining the effect of mutation of the contacted nucleotides on u-PAR promoter activity. Aim 3 will determine the role of extracellular signal-regulated kinases 1 (ERK1) and 2 or a constitutively activated MEK1 which lies upstream of the ERKs, to modulate u-PAR expression and in vitro invasion. Aim 4 will investigate the ability of a synthetic inhibitor of MEK1 activation to downregulate u-PAR expression and in vitro invasion, and Aim 5 will determine the role of the c-Jun aminoterminal kinase 1 (JNK1) in regulating u-PAR expression. It is hoped that these studies will benefit colon cancer patients by decreasing u-PAR expression in colon cancer and thereby reduce the metastatic spread of the disease.